Brain Research, 94 (1975) 337-346
337
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
R E C O V E R Y OF P A T T E R N D I S C R I M I N A T I O N A B I L I T Y IN RATS REC E I V I N G S E R I A L O R O N E - S T A G E V I S U A L C O R T E X LESIONS
PETER D. SPEAR AND HELEN BARBAS*
Department of Psychology, Kansas State University, Manhattan, Kansas 66506 (U.S.A.) (Accepted March 19th, 1975)
SUMMARY
Two groups of l0 hooded rats were trained on a pattern discrimination between horizontal and vertical striped stimuli which were equated for contour-length and total luminous flux, and in which consistent local luminous flux cues were eliminated. In one group of rats, visual cortex removals were performed in two stages with training between the operations. Nine out of the 10 rats were able to relearn the pattern discrimination (median of 344 trials) after the completed bilateral visual cortex removals. The second group of rats received similar bilateral visual cortex lesions in one stage. In agreement with previous studies, none of these animals were able to relearn the discrimination after more than 10 times (550 trial limit) the trials required for original learning. However, several rats with total one-stage lesions could relearn the pattern discrimination if very extended periods of training were given.
1N T R O D U C T I O N
After total removal of visual cortex, animals are able to recover some of the visual capacities which were lost as a result of the lesion. Rats, golden hamsters, hedgehogs, cats, tree shrews, and rhesus monkeys lacking visual cortex all have shown an ability to perform visual form and pattern discriminations between stimuli which have equal total luminous flux 4,6-8,12,21,24,27,28,31-33,35,40-43. Studies in several species indicate that differences in total length of the contours between the patterns to be discriminated are important for this ability7,24, 4°,41, and consistent local luminous flux differences between the stimuli also may be used if they are available 42. In the rat, successful pattern discrimination following removal of visual cortex has been limited * Now at the Neurophysiological Laboratories, Allan Memorial Institute, McGill University, Montreal, Canada.
338 to stimuli in which differential contour-length cues were available to the animals4,", ~1, 24. An example is a discrimination between vertical stripes and a homogeneous gray stimulus of equal total luminous flux 6. When stimuli have been used in which differential length of contour as well as total luminous flux cues were eliminated, such as a discrimination between vertical and horizontal stripes, rats lacking visual cortex have been unable to learn the task 2 4,13,17,19,20,37,39. The present study investigated whether a procedure known to facilitate recovery after brain damage in other situations would make it possible for rats to learn a task in which contour-length cues as well as luminous flux cues are eliminated. Previous studies in a variety of species and brain regions have shown that if an area of the brain is damaged in two sequential unilateral lesions, behavioral recovery may be improved; although in some cases training may be required between the two operations (see refs. 9 and 23 for reviews). For example, using a brightness discrimination task, rats which have the visual cortex of one hemisphere removed, followed by retraining and then removal of the remaining visual cortex in the opposite hemisphere, relearn more rapidly than rats which receive the same amount of brain damage in a single operation 11,29,30,36. In this case, as in most other studies showing improved recovery after serial lesions, the task employed was one which was clearly within the capacity of the organism after one-stage tesions% We asked whether this procedure could be used to produce behavioral recovery of a pattern discrimination task which in the past has proved impossible for rats with visual cortex damage. METHODS
Subjects The subjects were 20 adult male Long-Evans hooded rats, 90-120 days old at the beginning of the experiment. They were housed in individual cages with ad libitum food and water.
Apparatus and training A 2-choice shock avoidance box, similar to that described by Thompson and Bryant 38 was used for discrimination training. It consisted of a start box (10 cm wide × 20 cm long) which was separated from a choice box by a black plexiglas guillotine door which could be lifted to begin a trial. The choice box (40 cm tong and increasing in width from 10 cm at the start box to 30 cm at the choice point) and a goal box (30 cm × 30 cm) were separated by two stimulus doors which could be knocked down by subjects to enter the goal compartment. A 5 cm long divider separated the two stimulus doors. The floor of the start and choice compartments consisted of a stainless steel grid which could be electrified (0.2--0.4 mA). The stimulus doors were 9 em square with 8 alternating black (0.03 mL intensity) and white (0.95 mL)stripes (1.125 cm wide) oriented either horizontally or vertically. Total luminous flux and length of contour were equal for the two stimuli. Consistent trial to trial local flux cues were eliminated by varying which border of each stimulus was black or white on each trial according to a Gellerman 1° series. Position of the
339 horizontal and vertical doors also was varied from left to right on each trial according to different sets of Gellerman series. Several different Gellerman series were employed so that the rats could not learn the sequence of trials with extensive training. The doors were removed and reinserted following every trial in order to eliminate auditory cues as to whether the correct stimulus position was the same or had been shifted on the next trial. The stimuli were washed frequently and each door was interchangeably used as the horizontal or vertical stimulus in order to eliminate differential olfactory cues on the doors. Details of the pretraining and training procedures are described elsewhere 34. Briefly, the rats first were habituated to the apparatus, and then pretrained to escape and avoid shock in the choice compartment by displacing gray stimulus doors and retreating into the goal compartment, During training, the grid was charged 5 cm in front of the locked negative (vertical) stimulus, and it was not charged in front of the unlocked positive (horizontal) door. The rats were required to run from the start box, through the choice box and into the goal box via the correct stimulus door. Failure to leave the start box within 5 sec resulted in mild shock to the feet. If the rats remained in the choice compartment for 30 sec, shock was repeated until they escaped into the goal box. The rats received footshock and an error was recorded if the nose approached within 5 cm of the incorrect stimulus door. If an incorrect choice was made, the rats were allowed to shift and enter the goal box through the correct stimulus door. Following each trial, the rats were removed from the goal box and transferred to a cage for an intertrial interval of at least 90 sec. Each rat received 25 trials a day until a criterion of 18/20 correct choices was achieved.
Procedure The rats were randomly assigned to a serial unilateral or a one-stage bilateral lesion group, with the limitation that 10 rats would be assigned to each group. The sequence of events for the rats in each group are shown in Table I. Preoperatively, rats in both groups were trained to criterion on the horizontal-vertical pattern discrimination (acquisition, days 1-6). Following acquisition, rats in the serial lesion group underwent unilateral removal of the visual cortex of the right hemisphere (day 7). Ten days later, the rats in both groups were retrained to criterion (retention 1, days 17-18). Additional overtraining trials were given to equalize the number of training trials for all rats. Each rat received a total of 50 trials during the first retention test. The following day (day 19), rats in both groups were subjected to surgical procedures. Rats in the serial lesion group underwent removal of the visual cortex in the left hemisphere. Rats in the bilateral group received a one-stage lesion involving the visual cortex of both hemispheres. At this time the total extent of the lesion was identical for the two groups. Ten days following surgery (retention 2, day 29) all rats began retraining to an 18/20 criterion or 550 trials, whichever came first.
Surgery and histology The animals were anesthetized with Equi-Thesin (Jensen-Salsbery Labs.), injected intraperitoneally (0.3 ml/1O0 g). Visual cortex removals were performed by
340
Fig. 1. Dorsal view of the brain of each rat showing scale drawings of the visual cortex lesions. Above each brain is a diagram of a coronal section through the LGD which represents the extent of retrograde degeneration for each rat. Black in the LGD diagram indicates complete retrograde degeneration. In cases where scattered healthy appearing cells were present, their locus is shown by striations in the LGD diagrams. For reference to the learning data in Table I, each rat's number is indicated to the lower left of each brain. Scale markings on each brain in mm.
aspiration after retraction of the overlying meninges. In each hemisphere, the intended lesion extended from the posterior tip of the occipital pole to 4.5 mm anterior from lambda, and 1.5 mm from the midsagittalsuture to 7 mm laterally. This was intended to include all of areas 17, 18, and 18a according to the cytoarchitectural study of Krieg 16 and all of the primary and extraprimary visual areas according to electrophysiological mapping studiesl,~5,z6. Postoperatively the rats were injected intramuscularly with 100,000 U of bicillin (Wyeth Labs.). For histological preparation the rats were given a lethal dose of Equi-Thesin and were perfused through the heart with 0.9 ~ saline followed by 10 ~ formol-saline. The brain was removed from the skull and scale drawings were made of the lesions on standard diagrams of the dorsal view of the rat brain. After embedding in celloidin, the brains were sectioned at 30 pm. Every fifth section through the dorsal lateral geniculate nucleus (LGD) was mounted and stained with cresyl violet, Retrograde degeneration in the L G D was assessed.
341 RESULTS
Histology Fig. 1 shows scale drawings of the lesions for each rat. Measurements of the cortical lesion size indicated no asymmetry between the two hemispheres for either serial or bilateral lesion groups. In addition, no difference with regard to lesion size was found between the two groups of rats. For rats with serial lesions, median lesion size for left and right hemispheres were 28.19 m m square and 27.89 m m square, respectively. For the bilateral group, the measures were 27.28 m m square and 25.56 mm square. Diagrams of the extent of retrograde degeneration in the L G D for each rat are shown in Fig. 1. Seven of the rats in each group had complete retrograde degeneration of the E G D bilaterally, indicating that striate cortex had been completely removed 18, 19. In 3 of the rats in each group, a small region of scattered healthy appearing cells was observed in L G D which otherwise were completely degenerated. The density of these cells always was less than in the normal L G D . However, these regions may represent sparing of visual cortex. In no case was there localized sparing in the L G D with normal cell density.
Behavior Table ! presents the number of trials and errors required for learning and relearning the pattern discrimination for individual rats in the 2 groups. Statistical comparisons between the groups were made using Mann-Whitney tests (2-tailed). For preoperative acquisition, no significant differences were found between the two groups for either trials or errors to criterion. The retention 1 test compares the retention of the serial group after a unilateral lesion with that of the bilateral group prior to any lesion. The bilateral group is, therefore, a normal control group at this stage. Retention 1 criterion levels were reached by both groups with considerable savings. However, the serial group required a significantly greater number of trials (P < 0.02) and errors (P < 0.02) to reach criterion on retention 1 than the bilateral group. Therefore, it is concluded that the unilateral visual cortex ablation produced a slight retention deficit. The retention 2 test c~mpares both groups after bilateral visual cortex removal. As in previous studies, there was a marked loss of the discrimination following the one-stage bilateral visual cortex lesion. None of the rats with one-stage bilateral lesions relearned the discrimination within 550 trials, more than 10 times the number of trials required in original learning. Further, only one of these rats (No. 18) showed any improvement above chance performance within this number of trials. The rats with serial unilateral lesions also showed a loss of the discrimination following the second unilateral lesion. However, 9 out of 10 rats with serial unilateral lesions were able to relearn the pattern discrimination to the 18/20 criterion in from 177 to 536 trials. The two groups were significantly different in trials to criterion (P < 0.C02) and errors (P < 0.002).
342 TABLE I TIME SCHEDULE AND TRIALS AND ERRORS REQUIRED TO REACH CRITERION* FOR PREOPERATIVE ACQUISITION, FIRST RETENTION TEST, AND SECOND RETENTION TEST FOR RATS RECEIVING SERIAL UNILATERAL OR ONE-STAGE BILATERAL VISUAL CORTEX LESIONS
Days
Rat No.
1-6
7
17-18
19
29-
Acqu~itmn
U
Retentmn 1
U
Retention 2**
T
E
T
E
T
E
76 45 48 66 45 48 45 46 44 111
20 14 12 25 13 15 13 14 13 34
20 26 24 46 28 32 21 25 29 18
2 5 4 9 7 8 3 4 4 0
398 237 220 550 177 536 448 290 492 270
179 97 86 289 7t 220 159 122 168 106
47
14
25.5
4
344
140.5
2 3 6 7 9 13 15 16 18 20
48 40 98 58 47 57 37 48 51 44
19 9 27 19 16 16 10 12 15 14
19 18 19 18 19 20 19 20 19 18
1 0 1 0 1 2 1 2 1 0
550 550 550 550 550 550 550 550 550 550
328 323 333 284 323 328 306 318 274 308
Median
48
15.5
19
l
550
320.5
SERIAL GROUP
1 4 5 8 10 12 14 17 19 21 Median
B
BILATERAL GROUP
* Scores include the trials and errors in the criterion block. ** In retention 2, training was discontinued after 550 trials if criterion had not been reached. Abbreviations: B, bilateral visual cortex removal; U, unilateral visual cortex removal; T, trials; E, errors.
Additional training I t h a s b e e n s h o w n p r e v i o u s l y a~,4a t h a t w i t h s u f f i c i e n t t r a i n i n g u n d e r t h e p r o p e r conditions, cats with total removal of the visual cortex are able to learn a pattern d i s c r i m i n a t i o n b e t w e e n s t i m u l i e q u a t e d f o r t o t a l l u m i n o u s flux a n d a m o u n t o f c o n t o u r , a n d i n w h i c h n o l o c a l flux c u e s w e r e a v a i l a b l e . W i t h t h i s i n m i n d , a n a t t e m p t w a s made to determine if rats with one-stage bilateral removal of the visual cortex could relearn the pattern discrimination task if given sufficient training. F o u r r a t s f r o m t h e b i l a t e r a l g r o u p w e r e g i v e n 300 a d d i t i o n a l t r a i n i n g t r i a l s b e -
343 yond the 550 trial limit of retention 2. Two of these animals relearned the discrimination to criterion within this additional training period (rat 20: 7913 trials and 393 errors; rat 18:551 trials and 274 errors). A third rat (No. 13) improved to be consistently above chance performance, although criterion was not attained. The fourth rat (No. 15) did not show any improvement within the additional 3130 trials. DISCUSSION
These results show that rats lacking striate and extrastriate visual cortex (areas 17, 18 and 18a) can relearn a horizontal-vertical pattern discrimination between stimuli equated for total luminous flux and amount of contour, and in which no local flux cues are available. This confirms earlier reports using cats 35,4a. Thus, while these cues may be important for discrimination performance when they are available 7,24, 40-42, they are not necessary for successful discrimination in absence of visual cortex. In addition, the results show that serial lesions can result in reduced impairment of behavioral functions on which animals with one-stage lesions are extremely retarded, as well as of behaviors which are easily relearned after one-stage lesions% Earlier experiments with rats failed to show recovery of pattern discrimination tasks similar or identical to the horizontal-vertical problem used in the present experiment 2 4,13,17,19,20,37,39 These studies all discontinued postoperative training after 300 trials or less. Our results are consistent with previous work in that all but one of our rats with one-stage lesions were still at chance levels of performance after as many as 550 trials. Only after very extended periods of training were two of the rats able to reach criterion. However, note that the reduced impairment which we were able to show following serial unilateral lesions was not dependent upon unusually extended periods of postoperative training. Even if we had discontinued training after 3130 trials as others have done, 5 of the 10 rats with serial lesions would already have reached criterion (Table I) and 3 others would have been at better than chance performance. A factor which should be considered in light of these results is the amount of time allowed for recovery from the initial damage. In our experiment, both the serial and the one-stage bilateral groups received their first retention test, their last lesion, and the second retention test following exactly the same periods of time (Table I). In this way, the retention period between their last contact with the discrimination task (retention 1) and final postoperative testing (retention 2) was the same for both groups, a procedure which is crucial if comparisons of postoperative retention are to be made between the two groups of rats. This procedure also allowed both groups of rats the same recovery time (10 days) from their last lesion to postoperative retention testing, so that any generalized postoperative trauma at the time of testing was the same for rats in both groups. A consequence of this design, however, is that the rats with serial lesions received their first operation 12 days earlier than rats with a onestage lesion. If recovery from brain damage is a result of some specific process which is triggered by initial damage to the system, then the rats with serial lesions may show reduced impairment because this recovery process has had a longer time to operate. Further, the few rats with one-stage bilateral lesions which were able to relearn the
344 discrimination after extended training may have done so because of the added recovery time this involved, rather than because of the extended training itself. Two observations from the literature indicate that the time elapsed since the initial brain damage is probably not the relevant factor in these results. First, prewous studies indicate that the serial lesion effect is not dependent upon the total length of recovery following the initial lesion (although the time between sequential lesions is important)L For example, 2 studies29, '~0 have compared the effects on a 2-choice brightness discrimination of serial unilateral visual cortex lesions and one-stage bilateral lesions where each group of rats received their initial lesion at the same time. A reduced postoperative loss of the brightness discrimination was observed for the rats with serial unilateral lesions. Second, previous studies which have found no recovery of pattern discrimination ability in rats with visual cortex lesions allowed substantially longer recovery times following surgery than in the present experiment. In 4 different experiments which used horizontal-vertical pattern stimuli nearly identical to ours z-4,37 the rats were allowed from approximately 30 to over 90 days between one-stage bilateral visual cortex lesions and postoperative training. This is longer than the time allowed after either the first lesion for the serial group (22 days) or the single lesion for the bilateral group (10 days) in the present experiment, even if the time involved in the extended training given our rats with one-stage lesions is included. Nevertheless, none of a total of 19 rats used in the previous studies were able to learn the pattern discrimination within 1(30-3130 triats2-4,37. Thus, the recovered pattern discrimination ability of the rats with one-stage lesions which were given very extended training in our experiment is not likely to be a result of the extended recovery time this involved, but rather of the training itself. Further, the superior performance of the rats with serial lesions is undoubtedly a consequence of the serial lesion procedure per se, rather than any advantage due to added recovery time since the first lesion. The mechanisms by which serial lesions to the brain result in reduced behavioral impairments are unknown, though several hypotheses have been proposed 9. Whatever their nature, the present results indicate that these mechanisms apply to 2-choice pattern discrimination functions of the visual system, as well as to conditioned avoidance responses to light onsetS,14, 22 and 2-choice brightness discrimination functions TM eg,30,a6. Previous studies suggest that specific interoperative practice on the discrimination is necessary to observe sparing of 2-choice brightness discriminations following serial unilateral lesionsll,a.s,36, but that specific practice is not necessary with a conditioned avoidance responseS,14,2L Our animals received specific practice on the pattern discrimination between the two sequential lesions, and it would be of interest to know whether this is a necessary condition for the sparing which was observed on this task as well. A factor which may be important for the recovery that was observed both for rats with serial lesions and for those with one-stage lesions is the extent of the lesion beyond visual cortex. Our lesions were confined to visual cortex as defined electrophysiologically 1,25,26 and anatomically16,18. In the past, complete posterior decortications typically have been performed, including the areas surrounding visual cortex.
345 It is pessible that these s u r r o u n d i n g areas are involved in the recovery. This has been sho wn to be the case for r e c o v e r y o f p a t t e r n d i s c r i m i n a t i o n in cats following d a m a g e to visual cortical areas 17, 18 and 19 (ref. 43), and it also m a y be the case for rats. ACKNOWLEDGEMENTS S u p p o r t e d by U . S . P . H . S . G r a n t s 5 R01 EY01170 and MHC8359, a U . S . P . H . S . Biomedical Sciences S u p p o r t G r a n t , and a g r a n t f r o m the Kansas State U n i v e r s i t y B u r e a u o f G e n e r a l Research. ADDENDUM Af t er s u b m i s s i o n o f the present paper, a r e p o r t by D r u et al. s'~ apFeared concerning effects o f serial visual cortex lesions on p a t t e r n d i scr i m i n at i o n s in rats. Their results are consistent with those r e p o r t e d in the present paper.
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© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
R E C O V E R Y OF P A T T E R N D I S C R I M I N A T I O N A B I L I T Y IN RATS REC E I V I N G S E R I A L O R O N E - S T A G E V I S U A L C O R T E X LESIONS
PETER D. SPEAR AND HELEN BARBAS*
Department of Psychology, Kansas State University, Manhattan, Kansas 66506 (U.S.A.) (Accepted March 19th, 1975)
SUMMARY
Two groups of l0 hooded rats were trained on a pattern discrimination between horizontal and vertical striped stimuli which were equated for contour-length and total luminous flux, and in which consistent local luminous flux cues were eliminated. In one group of rats, visual cortex removals were performed in two stages with training between the operations. Nine out of the 10 rats were able to relearn the pattern discrimination (median of 344 trials) after the completed bilateral visual cortex removals. The second group of rats received similar bilateral visual cortex lesions in one stage. In agreement with previous studies, none of these animals were able to relearn the discrimination after more than 10 times (550 trial limit) the trials required for original learning. However, several rats with total one-stage lesions could relearn the pattern discrimination if very extended periods of training were given.
1N T R O D U C T I O N
After total removal of visual cortex, animals are able to recover some of the visual capacities which were lost as a result of the lesion. Rats, golden hamsters, hedgehogs, cats, tree shrews, and rhesus monkeys lacking visual cortex all have shown an ability to perform visual form and pattern discriminations between stimuli which have equal total luminous flux 4,6-8,12,21,24,27,28,31-33,35,40-43. Studies in several species indicate that differences in total length of the contours between the patterns to be discriminated are important for this ability7,24, 4°,41, and consistent local luminous flux differences between the stimuli also may be used if they are available 42. In the rat, successful pattern discrimination following removal of visual cortex has been limited * Now at the Neurophysiological Laboratories, Allan Memorial Institute, McGill University, Montreal, Canada.
338 to stimuli in which differential contour-length cues were available to the animals4,", ~1, 24. An example is a discrimination between vertical stripes and a homogeneous gray stimulus of equal total luminous flux 6. When stimuli have been used in which differential length of contour as well as total luminous flux cues were eliminated, such as a discrimination between vertical and horizontal stripes, rats lacking visual cortex have been unable to learn the task 2 4,13,17,19,20,37,39. The present study investigated whether a procedure known to facilitate recovery after brain damage in other situations would make it possible for rats to learn a task in which contour-length cues as well as luminous flux cues are eliminated. Previous studies in a variety of species and brain regions have shown that if an area of the brain is damaged in two sequential unilateral lesions, behavioral recovery may be improved; although in some cases training may be required between the two operations (see refs. 9 and 23 for reviews). For example, using a brightness discrimination task, rats which have the visual cortex of one hemisphere removed, followed by retraining and then removal of the remaining visual cortex in the opposite hemisphere, relearn more rapidly than rats which receive the same amount of brain damage in a single operation 11,29,30,36. In this case, as in most other studies showing improved recovery after serial lesions, the task employed was one which was clearly within the capacity of the organism after one-stage tesions% We asked whether this procedure could be used to produce behavioral recovery of a pattern discrimination task which in the past has proved impossible for rats with visual cortex damage. METHODS
Subjects The subjects were 20 adult male Long-Evans hooded rats, 90-120 days old at the beginning of the experiment. They were housed in individual cages with ad libitum food and water.
Apparatus and training A 2-choice shock avoidance box, similar to that described by Thompson and Bryant 38 was used for discrimination training. It consisted of a start box (10 cm wide × 20 cm long) which was separated from a choice box by a black plexiglas guillotine door which could be lifted to begin a trial. The choice box (40 cm tong and increasing in width from 10 cm at the start box to 30 cm at the choice point) and a goal box (30 cm × 30 cm) were separated by two stimulus doors which could be knocked down by subjects to enter the goal compartment. A 5 cm long divider separated the two stimulus doors. The floor of the start and choice compartments consisted of a stainless steel grid which could be electrified (0.2--0.4 mA). The stimulus doors were 9 em square with 8 alternating black (0.03 mL intensity) and white (0.95 mL)stripes (1.125 cm wide) oriented either horizontally or vertically. Total luminous flux and length of contour were equal for the two stimuli. Consistent trial to trial local flux cues were eliminated by varying which border of each stimulus was black or white on each trial according to a Gellerman 1° series. Position of the
339 horizontal and vertical doors also was varied from left to right on each trial according to different sets of Gellerman series. Several different Gellerman series were employed so that the rats could not learn the sequence of trials with extensive training. The doors were removed and reinserted following every trial in order to eliminate auditory cues as to whether the correct stimulus position was the same or had been shifted on the next trial. The stimuli were washed frequently and each door was interchangeably used as the horizontal or vertical stimulus in order to eliminate differential olfactory cues on the doors. Details of the pretraining and training procedures are described elsewhere 34. Briefly, the rats first were habituated to the apparatus, and then pretrained to escape and avoid shock in the choice compartment by displacing gray stimulus doors and retreating into the goal compartment, During training, the grid was charged 5 cm in front of the locked negative (vertical) stimulus, and it was not charged in front of the unlocked positive (horizontal) door. The rats were required to run from the start box, through the choice box and into the goal box via the correct stimulus door. Failure to leave the start box within 5 sec resulted in mild shock to the feet. If the rats remained in the choice compartment for 30 sec, shock was repeated until they escaped into the goal box. The rats received footshock and an error was recorded if the nose approached within 5 cm of the incorrect stimulus door. If an incorrect choice was made, the rats were allowed to shift and enter the goal box through the correct stimulus door. Following each trial, the rats were removed from the goal box and transferred to a cage for an intertrial interval of at least 90 sec. Each rat received 25 trials a day until a criterion of 18/20 correct choices was achieved.
Procedure The rats were randomly assigned to a serial unilateral or a one-stage bilateral lesion group, with the limitation that 10 rats would be assigned to each group. The sequence of events for the rats in each group are shown in Table I. Preoperatively, rats in both groups were trained to criterion on the horizontal-vertical pattern discrimination (acquisition, days 1-6). Following acquisition, rats in the serial lesion group underwent unilateral removal of the visual cortex of the right hemisphere (day 7). Ten days later, the rats in both groups were retrained to criterion (retention 1, days 17-18). Additional overtraining trials were given to equalize the number of training trials for all rats. Each rat received a total of 50 trials during the first retention test. The following day (day 19), rats in both groups were subjected to surgical procedures. Rats in the serial lesion group underwent removal of the visual cortex in the left hemisphere. Rats in the bilateral group received a one-stage lesion involving the visual cortex of both hemispheres. At this time the total extent of the lesion was identical for the two groups. Ten days following surgery (retention 2, day 29) all rats began retraining to an 18/20 criterion or 550 trials, whichever came first.
Surgery and histology The animals were anesthetized with Equi-Thesin (Jensen-Salsbery Labs.), injected intraperitoneally (0.3 ml/1O0 g). Visual cortex removals were performed by
340
Fig. 1. Dorsal view of the brain of each rat showing scale drawings of the visual cortex lesions. Above each brain is a diagram of a coronal section through the LGD which represents the extent of retrograde degeneration for each rat. Black in the LGD diagram indicates complete retrograde degeneration. In cases where scattered healthy appearing cells were present, their locus is shown by striations in the LGD diagrams. For reference to the learning data in Table I, each rat's number is indicated to the lower left of each brain. Scale markings on each brain in mm.
aspiration after retraction of the overlying meninges. In each hemisphere, the intended lesion extended from the posterior tip of the occipital pole to 4.5 mm anterior from lambda, and 1.5 mm from the midsagittalsuture to 7 mm laterally. This was intended to include all of areas 17, 18, and 18a according to the cytoarchitectural study of Krieg 16 and all of the primary and extraprimary visual areas according to electrophysiological mapping studiesl,~5,z6. Postoperatively the rats were injected intramuscularly with 100,000 U of bicillin (Wyeth Labs.). For histological preparation the rats were given a lethal dose of Equi-Thesin and were perfused through the heart with 0.9 ~ saline followed by 10 ~ formol-saline. The brain was removed from the skull and scale drawings were made of the lesions on standard diagrams of the dorsal view of the rat brain. After embedding in celloidin, the brains were sectioned at 30 pm. Every fifth section through the dorsal lateral geniculate nucleus (LGD) was mounted and stained with cresyl violet, Retrograde degeneration in the L G D was assessed.
341 RESULTS
Histology Fig. 1 shows scale drawings of the lesions for each rat. Measurements of the cortical lesion size indicated no asymmetry between the two hemispheres for either serial or bilateral lesion groups. In addition, no difference with regard to lesion size was found between the two groups of rats. For rats with serial lesions, median lesion size for left and right hemispheres were 28.19 m m square and 27.89 m m square, respectively. For the bilateral group, the measures were 27.28 m m square and 25.56 mm square. Diagrams of the extent of retrograde degeneration in the L G D for each rat are shown in Fig. 1. Seven of the rats in each group had complete retrograde degeneration of the E G D bilaterally, indicating that striate cortex had been completely removed 18, 19. In 3 of the rats in each group, a small region of scattered healthy appearing cells was observed in L G D which otherwise were completely degenerated. The density of these cells always was less than in the normal L G D . However, these regions may represent sparing of visual cortex. In no case was there localized sparing in the L G D with normal cell density.
Behavior Table ! presents the number of trials and errors required for learning and relearning the pattern discrimination for individual rats in the 2 groups. Statistical comparisons between the groups were made using Mann-Whitney tests (2-tailed). For preoperative acquisition, no significant differences were found between the two groups for either trials or errors to criterion. The retention 1 test compares the retention of the serial group after a unilateral lesion with that of the bilateral group prior to any lesion. The bilateral group is, therefore, a normal control group at this stage. Retention 1 criterion levels were reached by both groups with considerable savings. However, the serial group required a significantly greater number of trials (P < 0.02) and errors (P < 0.02) to reach criterion on retention 1 than the bilateral group. Therefore, it is concluded that the unilateral visual cortex ablation produced a slight retention deficit. The retention 2 test c~mpares both groups after bilateral visual cortex removal. As in previous studies, there was a marked loss of the discrimination following the one-stage bilateral visual cortex lesion. None of the rats with one-stage bilateral lesions relearned the discrimination within 550 trials, more than 10 times the number of trials required in original learning. Further, only one of these rats (No. 18) showed any improvement above chance performance within this number of trials. The rats with serial unilateral lesions also showed a loss of the discrimination following the second unilateral lesion. However, 9 out of 10 rats with serial unilateral lesions were able to relearn the pattern discrimination to the 18/20 criterion in from 177 to 536 trials. The two groups were significantly different in trials to criterion (P < 0.C02) and errors (P < 0.002).
342 TABLE I TIME SCHEDULE AND TRIALS AND ERRORS REQUIRED TO REACH CRITERION* FOR PREOPERATIVE ACQUISITION, FIRST RETENTION TEST, AND SECOND RETENTION TEST FOR RATS RECEIVING SERIAL UNILATERAL OR ONE-STAGE BILATERAL VISUAL CORTEX LESIONS
Days
Rat No.
1-6
7
17-18
19
29-
Acqu~itmn
U
Retentmn 1
U
Retention 2**
T
E
T
E
T
E
76 45 48 66 45 48 45 46 44 111
20 14 12 25 13 15 13 14 13 34
20 26 24 46 28 32 21 25 29 18
2 5 4 9 7 8 3 4 4 0
398 237 220 550 177 536 448 290 492 270
179 97 86 289 7t 220 159 122 168 106
47
14
25.5
4
344
140.5
2 3 6 7 9 13 15 16 18 20
48 40 98 58 47 57 37 48 51 44
19 9 27 19 16 16 10 12 15 14
19 18 19 18 19 20 19 20 19 18
1 0 1 0 1 2 1 2 1 0
550 550 550 550 550 550 550 550 550 550
328 323 333 284 323 328 306 318 274 308
Median
48
15.5
19
l
550
320.5
SERIAL GROUP
1 4 5 8 10 12 14 17 19 21 Median
B
BILATERAL GROUP
* Scores include the trials and errors in the criterion block. ** In retention 2, training was discontinued after 550 trials if criterion had not been reached. Abbreviations: B, bilateral visual cortex removal; U, unilateral visual cortex removal; T, trials; E, errors.
Additional training I t h a s b e e n s h o w n p r e v i o u s l y a~,4a t h a t w i t h s u f f i c i e n t t r a i n i n g u n d e r t h e p r o p e r conditions, cats with total removal of the visual cortex are able to learn a pattern d i s c r i m i n a t i o n b e t w e e n s t i m u l i e q u a t e d f o r t o t a l l u m i n o u s flux a n d a m o u n t o f c o n t o u r , a n d i n w h i c h n o l o c a l flux c u e s w e r e a v a i l a b l e . W i t h t h i s i n m i n d , a n a t t e m p t w a s made to determine if rats with one-stage bilateral removal of the visual cortex could relearn the pattern discrimination task if given sufficient training. F o u r r a t s f r o m t h e b i l a t e r a l g r o u p w e r e g i v e n 300 a d d i t i o n a l t r a i n i n g t r i a l s b e -
343 yond the 550 trial limit of retention 2. Two of these animals relearned the discrimination to criterion within this additional training period (rat 20: 7913 trials and 393 errors; rat 18:551 trials and 274 errors). A third rat (No. 13) improved to be consistently above chance performance, although criterion was not attained. The fourth rat (No. 15) did not show any improvement within the additional 3130 trials. DISCUSSION
These results show that rats lacking striate and extrastriate visual cortex (areas 17, 18 and 18a) can relearn a horizontal-vertical pattern discrimination between stimuli equated for total luminous flux and amount of contour, and in which no local flux cues are available. This confirms earlier reports using cats 35,4a. Thus, while these cues may be important for discrimination performance when they are available 7,24, 40-42, they are not necessary for successful discrimination in absence of visual cortex. In addition, the results show that serial lesions can result in reduced impairment of behavioral functions on which animals with one-stage lesions are extremely retarded, as well as of behaviors which are easily relearned after one-stage lesions% Earlier experiments with rats failed to show recovery of pattern discrimination tasks similar or identical to the horizontal-vertical problem used in the present experiment 2 4,13,17,19,20,37,39 These studies all discontinued postoperative training after 300 trials or less. Our results are consistent with previous work in that all but one of our rats with one-stage lesions were still at chance levels of performance after as many as 550 trials. Only after very extended periods of training were two of the rats able to reach criterion. However, note that the reduced impairment which we were able to show following serial unilateral lesions was not dependent upon unusually extended periods of postoperative training. Even if we had discontinued training after 3130 trials as others have done, 5 of the 10 rats with serial lesions would already have reached criterion (Table I) and 3 others would have been at better than chance performance. A factor which should be considered in light of these results is the amount of time allowed for recovery from the initial damage. In our experiment, both the serial and the one-stage bilateral groups received their first retention test, their last lesion, and the second retention test following exactly the same periods of time (Table I). In this way, the retention period between their last contact with the discrimination task (retention 1) and final postoperative testing (retention 2) was the same for both groups, a procedure which is crucial if comparisons of postoperative retention are to be made between the two groups of rats. This procedure also allowed both groups of rats the same recovery time (10 days) from their last lesion to postoperative retention testing, so that any generalized postoperative trauma at the time of testing was the same for rats in both groups. A consequence of this design, however, is that the rats with serial lesions received their first operation 12 days earlier than rats with a onestage lesion. If recovery from brain damage is a result of some specific process which is triggered by initial damage to the system, then the rats with serial lesions may show reduced impairment because this recovery process has had a longer time to operate. Further, the few rats with one-stage bilateral lesions which were able to relearn the
344 discrimination after extended training may have done so because of the added recovery time this involved, rather than because of the extended training itself. Two observations from the literature indicate that the time elapsed since the initial brain damage is probably not the relevant factor in these results. First, prewous studies indicate that the serial lesion effect is not dependent upon the total length of recovery following the initial lesion (although the time between sequential lesions is important)L For example, 2 studies29, '~0 have compared the effects on a 2-choice brightness discrimination of serial unilateral visual cortex lesions and one-stage bilateral lesions where each group of rats received their initial lesion at the same time. A reduced postoperative loss of the brightness discrimination was observed for the rats with serial unilateral lesions. Second, previous studies which have found no recovery of pattern discrimination ability in rats with visual cortex lesions allowed substantially longer recovery times following surgery than in the present experiment. In 4 different experiments which used horizontal-vertical pattern stimuli nearly identical to ours z-4,37 the rats were allowed from approximately 30 to over 90 days between one-stage bilateral visual cortex lesions and postoperative training. This is longer than the time allowed after either the first lesion for the serial group (22 days) or the single lesion for the bilateral group (10 days) in the present experiment, even if the time involved in the extended training given our rats with one-stage lesions is included. Nevertheless, none of a total of 19 rats used in the previous studies were able to learn the pattern discrimination within 1(30-3130 triats2-4,37. Thus, the recovered pattern discrimination ability of the rats with one-stage lesions which were given very extended training in our experiment is not likely to be a result of the extended recovery time this involved, but rather of the training itself. Further, the superior performance of the rats with serial lesions is undoubtedly a consequence of the serial lesion procedure per se, rather than any advantage due to added recovery time since the first lesion. The mechanisms by which serial lesions to the brain result in reduced behavioral impairments are unknown, though several hypotheses have been proposed 9. Whatever their nature, the present results indicate that these mechanisms apply to 2-choice pattern discrimination functions of the visual system, as well as to conditioned avoidance responses to light onsetS,14, 22 and 2-choice brightness discrimination functions TM eg,30,a6. Previous studies suggest that specific interoperative practice on the discrimination is necessary to observe sparing of 2-choice brightness discriminations following serial unilateral lesionsll,a.s,36, but that specific practice is not necessary with a conditioned avoidance responseS,14,2L Our animals received specific practice on the pattern discrimination between the two sequential lesions, and it would be of interest to know whether this is a necessary condition for the sparing which was observed on this task as well. A factor which may be important for the recovery that was observed both for rats with serial lesions and for those with one-stage lesions is the extent of the lesion beyond visual cortex. Our lesions were confined to visual cortex as defined electrophysiologically 1,25,26 and anatomically16,18. In the past, complete posterior decortications typically have been performed, including the areas surrounding visual cortex.
345 It is pessible that these s u r r o u n d i n g areas are involved in the recovery. This has been sho wn to be the case for r e c o v e r y o f p a t t e r n d i s c r i m i n a t i o n in cats following d a m a g e to visual cortical areas 17, 18 and 19 (ref. 43), and it also m a y be the case for rats. ACKNOWLEDGEMENTS S u p p o r t e d by U . S . P . H . S . G r a n t s 5 R01 EY01170 and MHC8359, a U . S . P . H . S . Biomedical Sciences S u p p o r t G r a n t , and a g r a n t f r o m the Kansas State U n i v e r s i t y B u r e a u o f G e n e r a l Research. ADDENDUM Af t er s u b m i s s i o n o f the present paper, a r e p o r t by D r u et al. s'~ apFeared concerning effects o f serial visual cortex lesions on p a t t e r n d i scr i m i n at i o n s in rats. Their results are consistent with those r e p o r t e d in the present paper.
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